CN108017668A - A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof and purposes - Google Patents

A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof and purposes Download PDF

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CN108017668A
CN108017668A CN201610958782.9A CN201610958782A CN108017668A CN 108017668 A CN108017668 A CN 108017668A CN 201610958782 A CN201610958782 A CN 201610958782A CN 108017668 A CN108017668 A CN 108017668A
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phosphate sodium
creatine phosphate
water
crystal form
half compound
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CN108017668B (en
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曾佳烽
施小风
李宝莹
毛杰
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HARBIN LAIBOTEN PHARMACEUTICAL Co.,Ltd.
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Shanghai Huatuo Medical Science Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/222—Amides of phosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The invention belongs to pharmaceutical technology field, and in particular to a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof, contains 4.5 hydrones in the Creatine Phosphate Sodium crystalline hydrate.In the half compound X ray powder diffraction patterns of high four water of crystal form purity Creatine Phosphate Sodium of the present invention, there is characteristic diffraction peak at 2 θ angles at 7.6 ± 0.2 °, 14.5 ± 0.2 °, 15.5 ± 0.2 °, 17.3 ± 0.2 °, 18.6 ± 0.2 °, 21.7 ± 0.2 °, 22.8 ± 0.2 °, 24.7 ± 0.2 °, and the content of 6 hydrate crystal forms of 1.5 hydrate of Creatine Phosphate Sodium and Creatine Phosphate Sodium is below the test limit of X ray powder diffractometer conventional sweeps；After high four water of crystal form purity Creatine Phosphate Sodium, half compound is when 120 DEG C of heating 0.5 are small, diffraction maximum is not observed in X ray powder diffraction patterns, that is, is changed into amorphous.Four water of Creatine Phosphate Sodium, the half compound heat endurance of the present invention is significantly better than 4.5 hydrate process sample of Creatine Phosphate Sodium commercialized product and the crystallization reported, to storage, transport, using bringing great convenience, storing cost can be greatly lowered, while also improve the security of clinical practice.

Description

A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof and purposes
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and its Preparation method and purposes.
Background technology
Phosphocreatine (creatine phosphate) is the active material being had by oneself in human body, in the energy generation of contraction of muscle Play a significant role in thanking.It is the chemical energy store of cardiac muscle and skeletal muscle, and is used for synthesizing again for ATP.Clinically use Intramuscular injection or intravenous injection disodium creatine phosphate are abnormal to treat the myocardial metabolism under ischemic state, and in openheart surgery When will disodium creatine phosphate add cardioplegic solution in protect cardiac muscle.Disodium creatine phosphate as myocardial protective agent medicine Through at home and abroad listing using for many years, due to itself being body cell endogenous material, show by clinic application good Security.Exogenous disodium creatine phosphate is also applied in sports, for protecting skeletal muscle and cardiac muscle from thin Intracellular is damaged and is improved muscle function and recovers.Disodium creatine phosphate also has neuroprotection, and clinic display is to large area brain The nervous function of Infarction Patients has improvement result.
Since the aqueous solution of Creatine Phosphate Sodium is unstable, creatine, creatinine, Fosfocreatinine etc. are readily decomposed into, therefore, at present What it is in Clinical practice is Creatine Phosphate Sodium sterile powder injection.Purity requirement of the sterile powder injection to product is very high, in packing, storage Hide, to ensure that medicine does not change, decomposes in transportational process, the impurity that medicine transformation, decomposition produce can directly bring clinic The risk of application.Therefore high heat endurance is of great significance the medicine of powder-injection formulation.
For Creatine Phosphate Sodium there are a variety of crystalline hydrate crystal forms, that has reported has 7 hydrates of crystallization, 6 hydrates of crystallization, knot Brilliant 4.5 hydrates, 1.5 hydrates of crystallization etc., the injection Creatine Phosphate Sodium listed at present, is denoted as crystallization tetrahydrate, I Find actually main component be crystallization 4.5 hydrates.The medicinal crystal-form that 4.5 hydrates are Creatine Phosphate Sodiums is crystallized, other Hydrate is non-medicinal crystal-form at present.Since the heat endurance for listing handicraft product is poor, Chinese Pharmacopoeia version two in 2015 (page 1568, Creatine Phosphate Sodium item under) require cool dark place (meaning lucifuge and no more than 20 DEG C) to preserve.Lucifuge can pass through packaging Solve, less than 20 DEG C then need extra cooling measure, this is to storing, transporting, using very high cost and inconvenience is brought, together When also accordingly add the security risk of clinical practice.Therefore, the heat endurance tool of Creatine Phosphate Sodium listing sample how is improved It is significant.
The content of the invention
It is an object of the invention to provide a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound, to overcome Present clinical The problem of Creatine Phosphate Sodium handicraft product used is temperature sensitive and unstable.
To achieve these goals, the present invention provides following technical solution：
According to the first aspect of the invention, the present invention provides a kind of high four water of crystal form purity Creatine Phosphate Sodium of (1) formula Half compound, high four water of crystal form purity Creatine Phosphate Sodium, half compound meet the condition of following I~III at the same time：
I. high four water of crystal form purity Creatine Phosphate Sodium, half compound has the structural formula of (1) formula, is tied in molecule containing 4.5 Brilliant water；
II. in high four water of crystal form purity Creatine Phosphate Sodium, the half compound X-ray powder diffraction figure, 2 θ angles 7.6 ± 0.2°、14.5±0.2°、15.5±0.2°、17.3±0.2°、18.6±0.2°、21.7±0.2°、22.8±0.2°、24.7± There is characteristic diffraction peak at 0.2 °, the diffraction maximum at 18.6 ± 0.2 ° is known as a peaks, corresponding 2 θ angles numerical value is denoted as a；The Gao Jing The content of 6 hydrate crystal forms of 1.5 hydrate of Creatine Phosphate Sodium and Creatine Phosphate Sodium in four water of type purity phosphoric acid creatine sodium, half compound The test limit of X-ray powder diffraction instrument conventional sweep is below, i.e., described high four water of crystal form purity Creatine Phosphate Sodium, half compound X- In ray powder diffraction, 2 θ angles 8.4 ± 0.2 °, 12.1 ± 0.2 °, 13.6 ± 0.2 °, a+0.4 ± 0.05 ° and 12.7 ± Salt free ligands peak at 0.2 °；
III. after high four water of crystal form purity Creatine Phosphate Sodium, half compound is when 120 DEG C of heating 0.5 are small, X-ray powder Diffraction maximum is not observed in diffraction pattern, that is, is changed into amorphous.
X-ray powder diffraction instrument conventional sweep described in condition II refers to that in sweep speed be 1.2 °~12 °/min bars It is scanned under part.
High crystal form purity Creatine Phosphate Sodium described in this patent crystallizes four water, half compound purity height, 1.5 hydrate therein Crystal form and 6 hydrate crystal forms contents are extremely low, less than the test limit of X-ray powder diffraction instrument conventional sweep, i.e. in its X-ray The characteristic diffraction peak of other crystal forms is not observed in powder diffraction spectrum.
JOURNAL OF PHARMACEUTICAL SCIENCES 2014,103 (11):3688-3695 (hereinafter referred to as Document 1) in report, there were significant differences for the X-ray powder diffraction figure of Creatine Phosphate Sodium difference crystalline hydrate, and 4.5 hydrates are brilliant 2 θ angles of type 7.6 ± 0.2 °, 14.5 ± 0.2 °, 15.5 ± 0.2 °, 17.3 ± 0.2 °, 18.6 ± 0.2 °, 21.7 ± 0.2 °, 22.8 ± 0.2 °, 24.7 ± 0.2 ° etc. has characteristic diffraction peak (diffraction maximum at 18.6 ± 0.2 ° to be known as a peaks, corresponding 2 θ angles number Value is denoted as a).Creatine Phosphate Sodium crystallize 1.5 hydrate crystal forms 8.4 ± 0.2 °, 12.1 ± 0.2 °, 13.6 ± 0.2 °, 17.4 ± 0.2 °, there is characteristic diffraction peak in a+0.4 ± 0.05 ° etc. (wherein stronger 17.4 ± 0.2 ° of diffraction maximum exists with 4.5 hydrate crystal forms A faint diffraction maximum at this partly overlaps).Creatine Phosphate Sodium crystallize 6 hydrate crystal forms 12.7 ± 0.2 °, a+0.4 ± 0.05 ° etc. has characteristic diffraction peak.
Creatine Phosphate Sodium listing sample marker is crystallization tetrahydrate, it has been found that actual is the crystallization of low crystal form purity 4.5 hydrates, are mixed with 1.5 hydrate crystal forms of notable content, its X-ray powder diffraction collection as shown in Figures 2 and 3, can be bright Show and observe the characteristic diffraction peak containing 1.5 hydrate crystal forms, 2 θ angles exist in Fig. 2：8.443 °, 12.148 °, 13.632 °, 19.023 the diffraction maximum at °；2 θ angles exist in Fig. 3：Diffraction maximum at 8.386 °, 12.123 °, 13.564 °, 18.984 °.
A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound prepared by the present invention, when 120 DEG C of heating 0.5 are small, puts After being cooled to room temperature, X-ray powder diffraction test is carried out, does not observe obvious diffraction maximum (shown in Fig. 7) in obtained collection of illustrative plates, It is changed into amorphous.And the Creatine Phosphate Sodium reported in sample, or document 1 is listed to Creatine Phosphate Sodium and crystallizes 4.5 hydrates Sample, when 120 DEG C of heating 0.5 are small, let cool to room temperature, carries out X-ray powder diffraction test, in obtained collection of illustrative plates, phosphorus The characteristic peak that creatine acid sodium crystallizes 4.5 hydrates disappears, and shows the characteristic peak of 1.5 hydrate crystal forms.Show to be changed into and finish Brilliant 1.5 hydrate crystal forms (Fig. 8 and Fig. 9 shown in).
Document 1 and patent CN104109171A show that Creatine Phosphate Sodium crystallizes 1.5 hydrates, is Creatine Phosphate Sodium water Most stable of crystal form in compound, since its clinical practice is invalidated, cannot function as medicinal at present.We surprisingly send out under study for action For 4.5 hydrates being crystallized referring now to medicinal crystal-form Creatine Phosphate Sodium, four water of Creatine Phosphate Sodium, the half compound phase of high crystal form purity Than in the listing sample for the low crystal form purity for being mixed with 1.5 hydrates of crystallization, there is notable superior heat endurance.That is, For 1.5 hydrate of crystallization with high thermal stability, if be mingled in sample of the crystal form for 4.5 hydrates of crystallization, but go out Reduce the heat endurance of 4.5 hydrate sample entirety of crystallization with expecting.
We further investigate this, are surprised to find the sample of high crystal form purity with being contaminated with the low of 1.5 hydrate crystal forms Crystal form purity sample it is heated lose the crystallization water when, have entirely different mechanism.4.5 described in listing sample and document 1 Hydrate process sample, is easy for losing partially crystallizable water at slightly higher temperature, is first changed into 1.5 hydrate crystal forms, then Further dehydration at high temperature.And high four water of crystal form purity Creatine Phosphate Sodium, half compound described in this patent, losing the crystallization water The temperature of Shi Suoxu is higher, and is not as commercialized product, is first changed into 1.5 hydrates, but at higher temperatures More crystallizations water are quickly lost to be changed into amorphous (see embodiment 5).
High four water of crystal form purity Creatine Phosphate Sodium, half compound described in this patent, its thermogravimetric analysis experiment (TG) display, First stage weightlessness is higher, and second stage weightlessness is less, the weightlessness between about 150 DEG C~240 DEG C, and typically smaller than 5.0%.And Low crystal form purity Creatine Phosphate Sodium crystallizes the phosphoric acid flesh reported in 4.5 hydrates, including Creatine Phosphate Sodium listing sample and document 1 Sour sodium crystallizes 4.5 hydrate samples, in the first zero-g period, only loses partially crystallizable water, is changed into 1.5 hydrate crystal forms, Second stage loses the crystallization water in 1.5 hydrates this part crystal forms again, and the weightlessness between about 150 DEG C~240 DEG C is usually big In 5.0%.
Creatine Phosphate Sodium listing sample is powder-injection, using closed glass bottle packaging.When environment temperature rise, if hot Stability is poor, then is easy to lose the crystallization water, the moisture of separate out in closed vessel, it is impossible to escape, can be in microcosmic office Portion forms solution (pH 8~9), and Creatine Phosphate Sodium is highly unstable in aqueous solutions of the pH below 9, so as to cause part phosphoric acid The fast decoupled of creatine sodium.As described in Example 8, when 70 DEG C of placements 2 are small, the high crystal form purity phosphocreatine described in this patent Sodium crystallizes 4.5 hydrates, and appearance remains unchanged, good fluidity, and related material increase is atomic；And list described in sample and document 1 4.5 hydrate process sample of crystallization, appearance seriously lumps, and related content of material dramatically increases.High crystal form described in this patent Four water of purity phosphoric acid creatine sodium, half compound relative to listing sample and and document 1 described in 4.5 hydrate process sample of crystallization, tool There is superior heat endurance.Transport, storage in hot weather, without doing special low temperature environment processing.
It has been surprisingly found that when a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in this patent is mixed on a small quantity Creatine Phosphate Sodium crystallizes 1.5 hydrates, even if the content of 1.5 hydrates of crystallization only accounts for 0.05% (mass percent), can all make Great variety occurs for the physical property of overall material, and heat endurance significantly reduces (shown in embodiment 10 and 11).120 DEG C of heating 0.5 it is small when after, X-ray powder diffraction figure be shown as crystallization 1.5 hydrates characteristic diffraction peak, its thermogravimetric analysis experiment (TG), More weightlessness (being more than 5.0%) is shown between weightless second stage, about 150 DEG C~240 DEG C.Its property become and on 4.5 hydrate samples described in city's sample and document 1 are consistent, and heat endurance is significantly reduced.It is mixed with 0.05% crystallization, 1.5 water 4.5 hydrate samples of compound, due to the relatively low (Chinese Pharmacopoeia 2015 edition four the 56th of the sensitivity of X-ray powder diffraction method Page, " can be identified in diffracting spectrum when impurity component content is more than 1% "), even if sweep speed is set to 1.2 °/min, The characteristic diffraction peak of 1.5 hydrate crystal forms of crystallization is not observed in X-ray powder diffraction figure yet.
Thus further demonstrate that, 4.5 hydrate crystal forms purity of Creatine Phosphate Sodium crystallization have heat endurance extremely notable Influence, while high crystal form purity Creatine Phosphate Sodium crystallize 4.5 hydrates, its crystal form purity can not be only from X-ray powder Diffraction pattern judges.Still have no better method at present at the same time and carry out the accurate purity for measuring crystal form.Discussion on according to this, Ke Yiyou Two following conditions crystallize 4.5 hydrates concisely to characterize the Creatine Phosphate Sodium of high crystal form purity：X-ray powder diffraction figure Only show the characteristic diffraction peak of 4.5 hydrate crystal forms in spectrum, while after sample is when 120 DEG C of heating 0.5 are small, X-ray powder spreads out Penetrate measure and be shown as amorphous.
Listing sample, which is substantially all, is mixed with 1.5 hydrate of crystallization that content is higher than more than X-ray powder diffraction test limit, Easily determine out from X-ray powder diffraction figure.And the Creatine Phosphate Sodium described in document 1 crystallizes 4.5 hydrate samples, The data provided according to document 1, can't see the characteristic diffraction peak of 1.5 hydrate crystal forms from X-ray powder diffraction figure；Thermogravimetric point Analysis display, it is weightless by the dehydration of first stage, it is changed into crystallizing 1.5 hydrates；When heating 0.5 is small in 90 DEG C of baking oven, It is changed into crystallizing 1.5 hydrates.From the point of view of the result for the crystal form combined experiments (embodiment 10 and 11) that this patent is implemented, it may infer that It is mixed with 1.5 hydrates of a small amount of crystallization, it crystallizes 1.5 hemihydrate contents and is less than X-ray powder diffraction test limit.
A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in this patent, its drying process easily control, When 50 DEG C or so dryings 1~2 are small, weight reaches constant, extends drying time weight and no longer reduces, is measured with Karl_Fischer method Moisture, and theoretical calculation.And sample is listed, Chinese Pharmacopoeia version two in 2015 (page 1568, Creatine Phosphate Sodium item under) moisture It is required that control, 20.0%~25.0%, in the drying process, dry terminal is not easy to judge, it is necessary in drying process listing sample In be repeatedly detected the water content of product, until 20.0%~25.0%.The reason is that with the extension of drying time, moisture constantly subtracts It is few, until being changed into 1.5 hydrates, shown in embodiment 12.
According to another aspect of the present invention, the present invention provides a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound Preparation method：
1) Creatine Phosphate Sodium is dissolved in 1~2 times of amount water, stirring and dissolving；
2) control system temperature is at 0~25 DEG C, stir it is lower add crystallization agent, be stirred for 1~5 it is small when；
3) filter, after filter cake is washed with 95% ethanol or absolute ethyl alcohol or acetone, dried through 40~60 DEG C of air streams, i.e., ；
The crystallization agent is methanol, 95% ethanol or absolute ethyl alcohol, and the volumetric usage of the crystallization agent is three times of water Or below three times.
Preferably, Creatine Phosphate Sodium is dissolved in 1~1.5 times of amount water in step 1), stirring and dissolving.
Preferably, control system temperature at 0~15 DEG C, stirs lower addition crystallization agent in step 2).
Preferably, the crystallization agent is methanol.
103012472 A of patent CN refer to the method for crystallising of Creatine Phosphate Sodium, but according to its disclosed preparation method not It can obtain four water of Creatine Phosphate Sodium, half compound of high crystal form purity.Such as in the embodiment of the present invention 2,95% ethanol body of crystallization agent When product is 5 times of water, obtained product is non-high four water of crystal form purity Creatine Phosphate Sodium, half compound.
If taking sterile working, so that high four water of crystal form purity Creatine Phosphate Sodium, half compound being prepared into is sterile production Product, are used to prepare aseptic powder injection, can be as the medicine of myocardial preservation.
Described in this patent a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and Creatine Phosphate Sodium listing sample and Compared with the 4.5 hydrate samples of described crystallization of document 1, there are significant difference, its crystal form purity is high, its heat endurance is much Better than Creatine Phosphate Sodium list sample and with document 1 it is described crystallization 4.5 hydrates (as shown in embodiment 8 and embodiment 9).
Creatine Phosphate Sodium crystallizes 1.5 hydrate crystal forms, is non-medicinal crystal-form at present although there is very high heat endurance, Mode, approach and the effect of clinical practice of its clinical practice all wait to verify, and the high crystal form purity phosphorus that this patent is invented Four water of creatine acid sodium, half compound, is the clinical practice crystal form of crystal form purity higher, clinic is may be directly applied to, since it has Superior thermal stability, can significantly reduce carrying cost and improve clinical application security.
Beneficial effects of the present invention：
1st, a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound provided by the invention, its crystal form purity is far above listing Sample.Character is stablized, and drying process easily controls.
2nd, a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound provided by the invention, heat endurance are significantly better than phosphoric acid Creatine sodium lists handicraft product and the 4.5 hydrate process sample of crystallization reported, to storage, transports, very big using bringing Facility, storing cost can be greatly lowered, while also improve the security of clinical practice.
3rd, a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and its characterizing method provided by the invention, can be effective It is pure less than the low crystal form of x-ray powder diffraction test limit to distinguish the product of low crystal form purity, especially 1.5 hemihydrate contents Spend product.
Statement " four water, half compound " in the present invention is equal with " 4.5 hydrate " connotation, that is, represents to contain in crystalline hydrate There are 4.5 hydrones.
" high four water of crystal form purity Creatine Phosphate Sodium, half compound " prepared by the present invention, is referred to as " the crystallization water in embodiment Compound 1 "
Brief description of the drawings
Fig. 1：The X-ray powder diffraction collection of crystalline hydrate 1；
Fig. 2：The X-ray powder diffraction collection of domestic listing sample 1；
Fig. 3：Import lists the X-ray powder diffraction collection of sample；
Fig. 4：Thermogravimetric analysis (TG) collection of illustrative plates of crystalline hydrate 1；
Fig. 5：Thermogravimetric analysis (TG) collection of illustrative plates of domestic listing sample 1；
Fig. 6：Import lists thermogravimetric analysis (TG) collection of illustrative plates of sample；
Fig. 7：Crystalline hydrate 1 respectively through 90 DEG C and 120 DEG C heating 0.5 it is small when after X-ray powder diffraction collection；
Fig. 8：Domestic listing sample 3 respectively through 90 DEG C and 120 DEG C heating 0.5 it is small when after X-ray powder diffraction collection；
Fig. 9：The X-ray powder diffraction collection of sample N (1.5 hydrates of crystallization)；
Figure 10:Crystalline hydrate 1- is ground with sample -0.05% in slow scanning (step-length 0.02 second, 1 second/step of sweep speed) Under the conditions of X-ray powder diffraction collection and respectively through 120 DEG C heating 0.5 it is small when after X-ray powder diffraction collection.
Embodiment
Technical scheme is described in further detail below in conjunction with specific embodiment.It is it should be noted that following real Apply example and be only exemplary description, and be not meant to limit the scope of the invention.It will be understood by those of ordinary skill in the art that Can to the technical solution technical scheme is modified or replaced equivalently of invention, without departing from the spirit and scope of technical solution of the present invention, It should all cover in scope of the presently claimed invention.
This patent implements capital equipment instrument used：
X-ray powder diffraction instrument, Bruker D8advance.
Thermogravimetric analyzer, NETZSCH TG 209F3.
Electric heating constant-temperature blowing drying box DGG-9076A, Shanghai Hui Lv scientific instrument Co., Ltd.
Karl Fischer Titrator, METTLER TOLEDO DL38.
Water isolation type constant incubator, GNP-9080 types, Shanghai precision experimental facilities Co., Ltd.
Domestic listing sample 1 is the injection Creatine Phosphate Sodium of Jilin Yinglian Biopharmaceutical Co., Ltd.'s production, batch Number：20150311.
The injection Creatine Phosphate Sodium that domestic listing sample 2 produces for Haikou Qili Pharmaceutical Co., Ltd., lot number： 20160401。
Domestic listing sample 3 is Harbin Laibotong Pharmaceutical Co., Ltd., the injection Creatine Phosphate Sodium of production, lot number 20160330
The injection Creatine Phosphate Sodium that import listing sample produces for Alfa Wassermann SPA, lot number： 14868。
" high four water of crystal form purity Creatine Phosphate Sodium, half compound " prepared by the present invention, is referred to as " knot in the examples below Brilliant hydrate 1 "
Embodiment 1
The preparation of crystalline hydrate 1.
20 grams of Creatine Phosphate Sodium, after adding 30ml water to dissolve, 10 DEG C of control system temperature, stirs lower addition 90ml methanol, stirs Mix 2 it is small when, filter, after solid is washed with 95% ethanol, under 50 DEG C of air streams dry 2 it is small when, up to crystalline hydrate 1.
Embodiment 2
According to the operating process of embodiment 1, change different experiment parameter conditions, the situation for obtaining product is shown in Table 1.
The product situation that 1 different technology conditions of table obtain
From the point of view of the preparation result of above different condition, when the amount for adding crystallization agent methanol is no more than the amount as aqueous solvent 3 times when, can obtain high four water of crystal form purity Creatine Phosphate Sodium, half compound, i.e. crystalline hydrate 1；When addition 95% second of crystallization agent When the amount of alcohol or absolute ethyl alcohol is no more than 3 times of the amount of the water as solvent, high four water of crystal form purity Creatine Phosphate Sodium can obtain Half compound.Under conditions of above-mentioned crystallization agent exceedes 3 times of solvent water, what is obtained is non-high crystal form purity Creatine Phosphate Sodium crystallization Four water, half compound.
Embodiment 3
By the obtained crystalline hydrate 1 of embodiment 1, domestic listing sample 1, domestic listing sample 2, domestic listing sample 3 and import listing sample carry out X-ray powder diffraction experiment, thermogravimetry (TG) experiment test respectively.
X-ray powder diffraction is tested：Instrument Bruker D8advance, service condition Cu (40kV, 40mA), scan model 3 °~40 ° are enclosed, 0.02 ° of scanning step, often walks 0.1 second.
X-ray powder diffraction experimental result：Only the feature of 4.5 hydrates of display crystallization is spread out in the collection of illustrative plates of crystalline hydrate 1 Peak is penetrated, sees Fig. 1.Except the feature diffraction of 4.5 hydrates of crystallization in the collection of illustrative plates of domestic listing sample 1~3 and import listing sample Outside peak, the characteristic diffraction peak of 1.5 hydrates of crystallization is all also mixed with, the representative collection of illustrative plates of domestic listing sample is shown in Fig. 2, import listing The collection of illustrative plates of sample is shown in Fig. 3.
Thermogravimetry (TG) is tested：Instrument, NETZSCH TG 209F3,30 DEG C~400 DEG C, heating rate 10K/min.
Thermogravimetry (TG) experimental result：TG collection of illustrative plates second stage weightlessness see the table below 2, the TG collection of illustrative plates second of crystalline hydrate 1 Step weight loss is less than 5.0%, and domestic listing sample 1~3 and import listing sample second stage weightlessness are all higher than 5.0%.Knot The TG collection of illustrative plates of brilliant hydrate 1 is shown in Fig. 4, and domestic listing sample representativeness TG collection of illustrative plates is shown in Fig. 5, and the TG collection of illustrative plates of import listing sample is shown in figure 6。
The TG percent weight loss of the different samples of table 2
Embodiment 4
The moisture for the crystalline hydrate 1 that embodiment 1 and embodiment 2 obtain is measured using Karl_Fischer method, measurement result is shown in Table 3.
The water content of 3 Karl_Fischer method determination sample of table
Sample Moisture Sample Moisture
1 sample of embodiment 24.22% 2 sample -7 of embodiment 24.16%
2 sample -1 of embodiment 24.68% 2 sample -9 of embodiment 24.23%
2 sample -2 of embodiment 24.10% 2 sample -10 of embodiment 24.35%
2 sample -3 of embodiment 24.85% 2 sample -11 of embodiment 24.66%
2 sample -6 of embodiment 23.97%
Karl_Fischer method measurement result shows, the moisture of crystalline hydrate 1, near 24.1%, with phosphocreatine Sodium crystallizes 4.5 hydrate theoretical water content values and coincide.
Embodiment 5
Two parts are taken by crystalline hydrate 1 that embodiment 1 obtains is parallel, and portion is open in 90 DEG C of drying boxes, and to place 0.5 small When, another in 120 DEG C of drying boxes it is open place 0.5 it is small when, be then cooled to room temperature in drier respectively, with reference to embodiment 3 condition, carries out X-ray powder diffraction measure.
As a result：After crystalline hydrate 1 is when 90 DEG C of dryings 0.5 are small, diffraction maximum has almost no change, and does not crystallize 1.5 water The diffraction maximum of compound occurs；After when 120 DEG C of dryings 0.5 are small, diffraction maximum disappears, and is changed into amorphous, as shown in Figure 7.
Embodiment 6
By domestic listing sample 1~3, import listing sample is parallel respectively takes two parts, and portion is open in 90 DEG C of drying boxes Place 0.5 it is small when, another in 120 DEG C of drying boxes it is open place 0.5 it is small when, be then cooled to room temperature in drier respectively, With reference to the condition of embodiment 3, X-ray powder diffraction measure is carried out.
As a result：After domestic listing sample 1~3 and import list sample when 90 DEG C of dryings 0.5 are small, its X-ray powder spreads out Penetrate 4.5 hydrate characteristic diffraction peaks original in collection of illustrative plates to weaken to disappearance, show the diffraction maximum of 1.5 hydrates of crystallization；At 120 DEG C After when drying 0.5 is small, the 4.5 hydrate characteristic diffraction peaks of its original disappear, and the diffraction maximum of 1.5 hydrates of crystallization is presented.Generation Table collection of illustrative plates (domestic listing sample 3) is shown in Fig. 8.
Embodiment 7
The method of bibliography 1 is prepared for sample N (1.5 hydrates of crystallization).Karl_Fischer method measures moisture, is 10.1%.X-ray powder diffraction measure is carried out to sample N, determination condition is with embodiment 3, as a result：As shown in figure 9, sample N is shown Now crystallize the diffraction maximum of 1.5 hydrates.
Embodiment 8
Stability comparative experiments.
The crystalline hydrate 1 that embodiment 1 is obtained using listing packaging and domestic listing sample 1, domestic listing sample 2, Domestic listing sample 3, import listing sample, in 70 DEG C of air dry oven, when placement 2 is small, detect the increase in relation to material Situation.It the results are shown in Table 4.
70 DEG C of stability datas of the different samples of table 4
The result shows that：When 70 DEG C of placements 2 are small, the related material of crystalline hydrate 1 has almost no change,
And the increase of remaining sample is obvious.
Embodiment 9
Stability comparative experiments.
The crystalline hydrate 1 that embodiment 1 obtains is packed using listing, 60 DEG C of constant temperature are placed on domestic listing sample -3 In drying box, in the 0th day, the 5th day, the 10th day sampling detection phosphocreatine and related material.The results are shown in Table 5：
60 DEG C of stability datas of the different samples of table 5
The result shows that：Crystalline hydrate 1 is placed 10 days at 60 DEG C, and related material increase is atomic, and lists the related thing of sample The increase of matter is extremely notable, and main composition decomposes serious.
Embodiment 10
Crystal form mixing comparative experiments one.
The crystalline hydrate 1 and sample N that embodiment 1 is obtained distinguish ground 200 mesh sieve, spare.
Take the crystalline hydrate 1 and sample N of a certain amount of excessively complete sieve respectively, make sample N account for both gross weights 2%, 0.5%th, 0.05%, the method that both are mixed using substep, grinds, and mixes, and crosses 200 mesh sieves, then mix.4 samples are obtained, It is denoted as sample -2%, sample -0.5%, sample -0.05%.Along with the crystalline hydrate 1 after grinding, crystalline hydrate is denoted as 1- is ground.When taking a certain amount of placement 0.5 open in 120 DEG C of baking oven small respectively in 4 samples, room is cooled in drier Temperature, obtains sample -2%-120, sample -0.5%-120, sample -0.05%-120, crystalline hydrate 1- and grinds -120.To front and rear Totally 8 samples carry out X-ray powder diffraction experiment, and experiment condition is the same as embodiment 3.It is again step-length by sweep speed parameter adjustment 0.02 degree, sweep speed 1.0 seconds/step, remaining is constant, measure under this condition crystalline hydrate 1- grind, sample -0.05%.It is right Preceding 4 samples carry out thermogravimetric analysis (TG) experiment.Experimental result see the table below, and part X-ray powder diffraction collection is shown in Figure 10.
XRPD the and TG results of the 6 difference amount of mixing of table
Note：XRPD experiments refer to X-ray powder diffraction experiment
Test result indicates that even if being mixed into 0.05% 1.5 hydrates in crystalline hydrate 1, physical property occurs Change.Although the X-ray powder diffraction collection before upon mixing, being heated does not observe change, 120 DEG C heat 0.5 it is small when after X-ray powder diffraction figure and thermogravimetric analysis (TG) test weightlessness between 150 DEG C~240 DEG C, lose original Feature.Even if this explanation, which is mixed into minimal amount of 1.5 hydrate crystal forms, can all influence to crystallize the relevant property of 4.5 hydrate thermostabilizations Matter.
Embodiment 11
Crystal form mixing comparative experiments two.
Sample in Example 10 respectively：Sample -2%, sample -0.5%, sample -0.05%, and after being ground up, sieved Crystalline hydrate 1 and sample N, using simulation listing packaging, in 70 DEG C of air dry oven, place 2 it is small when, detection it is related The increase situation of material.As a result it is as follows：
The stability data of the 7 difference amount of mixing of table
The result shows that even if four water of Creatine Phosphate Sodium, half compound of high crystal form purity has been mixed into 1.5 water of minimal amount of crystallization Compound, its heat endurance can significantly reduce.
Embodiment 12
Crystalline hydrate 1, import listing sample, domestic listing sample 1, the domestic listing sample 2 that embodiment 1 is obtained, 1 gram is taken respectively into measuring cup, it is accurately weighed.Opening is placed in 50 DEG C of air dry ovens, when 1 is small, 4 it is small when, it is 7 small When, take out, let cool in drier to room temperature, precise weighing, calculated weightless.It the results are shown in Table 8.
The loss on drying of the different samples of table 8
Crystalline hydrate 1, import listing sample, domestic listing sample 1, domestic listing sample 2, drip through karl Fischer moisture Determining the moisture that instrument measures is：24.22%, 22.43%, 23.16%, 22.67%.
Crystalline hydrate 1 after drying, then at 50 DEG C it is dry when, weight no longer changes substantially, and drying process is easy to control System.And list sample, when 50 DEG C are dry, when 5 is small in weight persistently reduce, after weightlessness is of about 14%, constant weight.But For moisture at this time not in the range of its quality standard defined (20.0%~25.0%), drying process is not easily-controllable System.
Embodiment 13
The preparation of injection crystalline hydrate 1
4.5 hydrate of 10kg Creatine Phosphate Sodiums is taken, adds water for injection 10kg, stirring and dissolving, 10 DEG C of control system temperature, adds 767 type activated carbons remove heat source, degerming with 0.22 μm of filtering with microporous membrane, add the methanol 30L through 0.22 μm of filtering with microporous membrane, Stir 3 it is small when, enter multifunctional filtering scrubbing-and-drying unit (three-in-one), filter, detergent is through 0.22 μm of filtering with microporous membrane 95% ethanol, after washed, filtering, leads to 60 DEG C of degerming hot-air dryings, sieving.Keep sample detection, Karl_Fischer method measure Moisture content, is 24.3%.Every bottle of 0.66g (phosphorous creatine acid sodium 0.5g), is sub-packed in cillin bottle, adds rubber plug aluminium lid to seal to obtain the final product.
In keeping sample, a certain amount of progress X-ray powder diffraction experiment is taken, experiment condition is with embodiment 3, and as a result collection of illustrative plates is only The characteristic diffraction peak of display 4.5 hydrates of crystallization, without 1.5 hydrates and 6 hydrate characteristic diffraction peaks.Separately take it is a certain amount of, in 120 DEG C baking oven in it is open place 0.5 it is small when, be cooled to room temperature in drier, carry out X-ray powder diffraction experiment, test bar Part is the same as embodiment 3.As a result collection of illustrative plates is shown without notable diffraction maximum, is amorphous.

Claims (8)

1. a kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound of (1) formula, high four water of crystal form purity Creatine Phosphate Sodium half Compound meets the condition of following I~III at the same time：
I. high four water of crystal form purity Creatine Phosphate Sodium, half compound has the structural formula of (1) formula, is crystallized in molecule containing 4.5 Water；
II. in high four water of crystal form purity Creatine Phosphate Sodium, the half compound X-ray powder diffraction figure, 2 θ angles 7.6 ± 0.2 °, 14.5±0.2°、15.5±0.2°、17.3±0.2°、18.6±0.2°、21.7±0.2°、22.8±0.2°、24.7±0.2° There is characteristic diffraction peak at place, the diffraction maximum at 18.6 ± 0.2 ° is known as a peaks, corresponding 2 θ angles numerical value is denoted as a；The high crystal form is pure The content for spending 6 hydrate crystal forms of 1.5 hydrate of Creatine Phosphate Sodium and Creatine Phosphate Sodium in four water of Creatine Phosphate Sodium, half compound is low In the test limit of X-ray powder diffraction instrument conventional sweep, i.e., described high four water of crystal form purity Creatine Phosphate Sodium, half compound X-ray In powder diffraction spectrum, 2 θ angles are in 8.4 ± 0.2 °, 12.1 ± 0.2 °, 13.6 ± 0.2 °, a+0.4 ± 0.05 ° and 12.7 ± 0.2 ° Locate salt free ligands peak；
III. after high four water of crystal form purity Creatine Phosphate Sodium, half compound is when 120 DEG C of heating 0.5 are small, X-ray powder diffraction Diffraction maximum is not observed in figure, that is, is changed into amorphous.
2. high four water of crystal form purity Creatine Phosphate Sodium, half compound according to claim 1, it is characterised in that：Its X-ray powder Last diffraction pattern is as shown in Figure 1.
3. high four water of crystal form purity Creatine Phosphate Sodium, half compound according to claim 1, it is characterised in that：Institute in condition II The X-ray powder diffraction instrument conventional sweep stated refers to be scanned under the conditions of sweep speed is 1.2 °~12 °/min.
4. a kind of preparation method of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in claim 1, including following step Suddenly：
1) Creatine Phosphate Sodium is dissolved in 1~2 times of amount water, stirring and dissolving；
2) control system temperature is at 0~25 DEG C, stir it is lower add crystallization agent, be stirred for 1~5 it is small when；
3) filter, after filter cake is washed with 95% ethanol or absolute ethyl alcohol or acetone, dried through 40~60 DEG C of air streams, to obtain the final product；
The crystallization agent is methanol, 95% ethanol or absolute ethyl alcohol, and the volumetric usage of the crystallization agent is the three times or three of water Below times.
A kind of 5. preparation method of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in claim 4, it is characterised in that： Creatine Phosphate Sodium is dissolved in 1~1.5 times of amount water in step 1), stirring and dissolving.
A kind of 6. preparation method of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in claim 4, it is characterised in that： Control system temperature stirs lower addition crystallization agent at 0~15 DEG C in step 2).
7. a kind of preparation method of high four water of crystal form purity Creatine Phosphate Sodium, half compound any one of claim 4-6, It is characterized in that：The crystallization agent is methanol.
A kind of 8. purposes of high four water of crystal form purity Creatine Phosphate Sodium, half compound described in claim 1, it is characterised in that：It is described Application of high four water of crystal form purity Creatine Phosphate Sodium, half compound in Creatine Phosphate Sodium sterile powder injection is prepared.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979697A (en) * 2019-12-17 2021-06-18 重庆圣华曦药业股份有限公司 Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012472A (en) * 2012-12-10 2013-04-03 天津大学 Crystal preparation method of creatine phosphate sodium

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012472A (en) * 2012-12-10 2013-04-03 天津大学 Crystal preparation method of creatine phosphate sodium

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JON R. HERRIOTT等: "The Crystal Structure of the Disodium Salt of N-Phosphorylereatine Hydrate", 《ACTA CRYST.》 *
YUN XU等: ""Solid-State Characterization and Transformation of Various Creatine Phosphate Sodium Hydrates"", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979697A (en) * 2019-12-17 2021-06-18 重庆圣华曦药业股份有限公司 Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof

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